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Transcriptomic analysis of human lens and age-related cataract

ABSTRACT: As an ageing population trend, age-related cataracts (ARC) continue to be the primary cause of reversible severe vision impairment and blindness worldwide, with an increasing incidence. The primary disease mechanism of ARC formation is metabolic abnormalities and oxidative stress mainly caused by increasing age. Additionally, ultraviolet B exposure, systematic disease factors (diabetes and hypertension), and lifestyle factors (smoking, drinking, and malnutrition) are the risk factors for ARC formation. Although surgical removal of the onset lens and replacement of the intraocular lens is currently the only effective treatment method with a high success rate and a high-cost fee, cataracts have so far lacked effective therapeutic drugs leading to a heavy burden on the patient's family and society. Therefore, we performed transcriptomic analysis of human lens and ARC to investigate the possible pathogenesis of lens opacification in ageing people.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213546 | GEO | 2023/02/23

REPOSITORIES: GEO

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Project description:Although majority of the genes linked to pediatric cataract exhibit lens fiber cell-enriched expression, our understanding of gene regulation in these cells is limited to function of just eight transcription factors and largely in the context of crystallins. Here, we identify small Maf transcription factors MafG and MafK as regulators of several non-crystallin human cataract genes in fiber cells and establish their significance to cataract. We applied a bioinformatics tool for cataract gene discovery iSyTE to identify MafG and its co-regulators in the lens, and generated various null-allelic combinations of MafG:MafK mouse mutants for phenotypic and molecular analysis. By age 4-months, MafG-/-:MafK+/- mutants exhibit lens defects that progressively develop into cataract. High-resolution phenotypic characterization of MafG-/-:MafK+/- lens reveals severe defects in fiber cells, while microarrays-based expression profiling identifies 97 differentially regulated genes (DRGs). Integrative analysis of MafG-/-:MafK+/- lens-DRGs with 1) binding-motifs and genomic targets of small Mafs and their regulatory partners, 2) iSyTE lens-expression data, and 3) interactions between DRGs in the String database, unravels a detailed small Maf regulatory network in the lens, several nodes of which are linked to human cataract. This analysis prioritizes 36 highly promising candidates from the original 97 DRGs. Significantly, 8/36 (22%) DRGs are associated with cataracts in human (GSTO1, MGST1, SC4MOL, UCHL1) or mouse (Aldh3a1, Crygf, Hspb1, Pcbd1), suggesting a multifactorial etiology that includes elevation of oxidative stress. These data identify MafG and MafK as new cataract-associated candidates and define their function in regulating largely non-crystallin genes linked to mouse and human cataract. Microarray comparision of lenses from mixed background (129Sv/J, C57BL/6J, and ICR) control (MafG+/-:MafK+/-; no-cataract) and compound (MafG-/-:MafK+/-; cataract) mouse mutants

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Transcriptomic analysis of human lens and age-related cataract

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